Small cell lung cancer (SCLC) has an overall prognosis of 6%, and novel therapies are desperately needed. Previously, we had shown c-Met receptor tyrosine kinase can be an important therapeutic target in SCLC. c-Met/HGF has been shown to be involved in proliferation, cell motility and migration, invasion, angiogenesis and metastasis of many solid tumors. Previously, we had identified mutations of c-Met in the juxtamembrane (JM) and semaphorin (Sema) domains of c-Met, and showed them to be gain-of-function mutations. Using C. elegans modeling system, we show that the JM domain c-Met mutants cause a dramatic phenotype related to the vulva, and is further activated with nicotine (an important component of cigarette smoke, and implicated in the pathogenesis for SCLC). In our initial proposal, we had looked at primary SCLC tumor tissues, but had not determined the mutation or amplification of c-Met in SCLC in primary tumor tissue as compared to metastatic tumor tissue (such as lymph nodes and distant metastases); this would be important to study since SCLC is highly metastatic. We had also determined specific inhibitors against c-Met, for which there are now several Phase I clinical trials. In our investigations, most recently, we have identified that c-Met can be activated by HGF, and the phosphorylated form can localize to the nucleus. Within the nucleus, phospho-c-Met can interact with various proteins such as topoisomerase-I and the transcription factor Pax 5. Interestingly, Pax 5 is expressed in SCLC and not non-SCLC; whereas, Pax 8 is expressed in non-SCLC and not SCLC. We now show that Pax 5 is a transcription factor for the c-Met gene in SCLC. Thus, to further study the role of c- Met in SCLC, we would propose to: 1. Determine the expression, mutational and amplification patterns of c-Met in primary versus metastatic SCLC; 2. Determine the role of nuclear c-Met in SCLC; 3. Determine the combinatorial targeting of c- Met, Pax5, and Topoisomerase-I in SCLC. With our initial success in defining the role of c-Met/HGF axis in SCLC, development of a number of biological and biochemical tools to study the c-Met pathway in SCLC, and new observations for c-Met in SCLC, we will dramatically impact on the biology and therapy for SCLC. PUBLIC HEALTH RELEVANCE: Small cell lung cancer (SCLC) is a difficult disease and novel targets are desperately needed. We have identified that c-Met receptor tyrosine kinase can be activated, mutated, or amplified, and can shuttle to the nucleus. In the nucleus, it binds to different proteins such as Pax5 and topoisomerase-I, and the studies proposed will dissect out mechanisms for this. Ultimately, we propose to bring to fruition combination therapies using these molecules.